A substrate cycle is produced when a non-equilibrium reaction in the forward direction is opposed by another non-equilibrium reaction in the reverse direction of the pathway. The two opposing reactions must be catalyzed by separate enzymes. When both enzymes are simultaneously active, chemical energy will be converted to heat, even though there may be no net flux of substrate. Substrate cycles have been demonstrated in in vitro studies and in a few animal studies, but not in humans. The difficulty in demonstrating their existence in humans is that the reactions occur intracellularly, and are therefore not easily studied in a non-invasive manner. It is our objective to study the dynamics of substrate cycles in vivo, primarily in human subjects. We will focus on three intra-cellular cycles: glucose/glucose 6P/glucose; fructose 6P/fructose dP/fructose 6P; and triglyceride/fatty acid/triglyceride. We will use tracer methodology and stable, non-radioactive isotopes of glucose (2-d, 3-d and 6, 6-d2- glucose), fatty acid (13C-palmitate), and glycerol (d-5 glycerol), and analysis by gas chromatography mass spectrometry. We will investigate the hormonal control of substrate cycles, and how substrate cycling may be involved in the metabolic alterations that occur in different physiological and pathological states. We will investigate in normal man the effects of cortisol, epinephrine, glucagon and insulin. Also, the effects of physical training on substrate cycling will be assessed, both in terms of responsiveness to hormonal stimulation and also in response to exercise. The effect of obesity on substrate cycling both basally and in response to hormonal stimulation will be determined, as well the effect of obesity on the response to a three-day fast. The role of substrate cycling in two "hypermetabolic" states will also be investigated. Severely burned patients will be studied before and immediately after treatment with propanolol, which will reduce the metabolic rate, and the role of substrate cycling in malignant hyperthermia in a pig model will be investigated. The wide clinical implications of substrate cycling are reflected by the diverse physiological states in which they have been proposed to play a role. The understanding of their regulation could provide important information regarding energy substrate metabolism, and the control of thermogenesis.